Serotonin (5-HT) is a neurotransmitter widely distributed throughout the body. Seven subtypes of serotonin are currently known. In particular, great attention has been focused on the elucidation of a 5-HT4 receptor and the confirmation of pharmaceutical action thereof.
In general, 5-HT4 receptor agonists are found to be therapeutically effective for the treatment of various disease conditions such as gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageal disease, nausea, central nervous system disease, Alzheimer's disease, cognitive impairment, emesis, migraine, neurological disease, pain, cardiovascular disorder, cardiac failure, cardiac arrhythmia, diabetes and apnea syndrome (See Tips, 1992, 13, 141; Ford A. P. D. W. et al., Med. Res. Rev., 1993, 13. 633; Gullikson G. W. et al., Drug Dev. Res., 1992, 26, 405; Richard M. Eglen et al., Tips, 1995, 16, 391; Bockaert J. et al., CNS Drugs, 1, 6; Romanelli M. N. et al., Arzheim Forsch./Drug Res., 1993, 43, 913; Kaumann A. et al., Naunyn-Schmiedeberg's. 1991, 344, 150; and Romanelli M. N. et al., Arzheim Forsch./Drug Res., 1993, 43, 913).
Despite extensive uses of 5-HT4 receptor agonists, there are little 5-HT4 receptor agonist compounds that are currently clinically used. To this end, there is a need for a 5-HT4 receptor agonist which is capable of exhibiting excellent medicinal effects while having minimum adverse side effects.
Benzamide derivatives have several prominent pharmacological actions. These excellent pharmacological activities of the benzamide derivatives are due to their effects on the nervous system which is controlled by serotonin that is a neurotransmitter. The role of serotonin, that is, the pharmacological action of benzamide derivatives has been broadly involved in a variety of diseases and conditions for many years. Further, a great deal of study and research has focused on production and storage sites of serotonin as well as the location of serotonin receptors in order to determine the relationship between the location of serotonin receptors and various disease states or conditions in humans.
Cisapride, which is a typical 5-HT4 receptor agonist, is one of benzamide derivatives. U.S. Pat. Nos. 4,962,115, 5,057,525 and 5,137,896 disclose N-(3-hydroxy-4-piperidinyl)benzamides including cisapride. These compounds are known to stimulate gastrointestinal motility. Further, U.S. Pat. No. 5,864,039 discloses benzamide derivatives.
To this end, the inventors of the present invention succeeded in the synthesis of novel benzamide derivatives which exhibit an agonistic activity via strong binding with a 5-HT4 receptor and good gastrointestinal absorption and which are capable of minimizing adverse side effects. The present invention has been completed based on this finding.